Overall Description (Applicant's Description) We have developed a multi- disciplinary program to investigate genetic susceptibility to childhood and associated cancer using genetic epidemiologic, cellular, and molecular techniques. The hypotheses are based on a multi-stage model for cancer, and are tested in two model familial syndromes of childhood and adolescent cancers, sarcomas and Li Fraumeni syndrome and its variants and Wilms' tumor of the kidney. or each tumor type, genetic loci have been identified that may be altered both as germline mutations and as tumor-specific mutations. There is also significant evidence for genetic heterogeneity, or involvement of additional cancer susceptibility loci. The underlying themes of the program include characterization of the underlying characterization of the underling cancer susceptibility, determination of the heritable contribution to each tumor, determination of the role and nature of genomic instability and genes that confer genomic instability in familial cancer syndromes, analysis of germline and somatic mutations by type and mechanism, development of animal models for human cancer susceptibility syndromes to explore evidence for modifier genes and developmental effects, and determination of the implications of germline mutations for the patients and their families. The findings from this program should provide insights into the mechanisms of carcinogenesis as well as guidelines for clinical programs for patients at high risk of cancer.